Sarcopenia. Группа авторов
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Apoptosis
There is strong evidence that apoptosis, the process of programmed cell death, plays a primary role in the pathogenesis of the age‐associated decline of muscle mass and strength. Studies that compared skeletal muscle tissues from younger and older rats reported high levels of apoptosis and connected the degree of muscle mass decline with the severity of apoptotic DNA fragmentation [80–82]. Apoptosis appears to be more frequent among type II fibers, possibly consequently to the higher susceptibility to TNF‐alpha signaling pathway. In skeletal muscle fibers, apoptosis can be induced either through a mitochondria‐independent or a mitochondria‐dependent mechanism, and it is not established which one of these pathways contributes to the accelerated decline of muscle mass and strength that eventually leads to sarcopenia. In mitochondria, apoptosis is initiated by mitochondrial matrix accumulation of Ca2+ which leads to the opening of the permeability transition pore (MPTP), a large non‐selective channel in the inner mitochondrial membrane. The opening of the MPTP increases concentrations of ROS, elicits membrane depolarization, and releases cytochrome c into the cytosol, activating the apoptotic program through a number of intermediate steps, including the activation of caspase‐9 and caspase‐3. Apoptosis includes reorganization of the cytoskeleton, arrest of cell replication, fragmentation of the nuclear membrane and the DNA, and eventually cell death. There is some but not concluding evidence that the threshold for apoptosis activation is increased in aging skeletal muscle, especially in humans. Further research is needed in this field. Interestingly, exercise and dietary restriction attenuate apoptosis with aging [81, 82]. Targeting apoptosis might be an effective intervention to counteract age‐related muscle wasting. However, more mechanistic studies are required before potentially effective treatment strategies can be developed.
Mitochondrial proteostasis mechanisms
A perfectly tuned control of the protein concentrations, quality control and recycling are essential for mitochondrial health. Such control is exerted by the ubiquitin‐proteasome system (UPS) and the autophagy–lysosome system. These catabolic mechanisms are modulated by the AMP‐Kinase and the FOXO transcription factor family, which inhibit MTORC1, the master regulator of protein synthesis and degradation. However, whether a dysregulation of this proteostasis mechanism leads to accelerated protein breakdown with aging, which results into a decline of muscle mass, or rather a failure of protein synthesis in replacing the degraded proteins, is currently unknown. Discovery proteomics studies in human muscle have found a substantial underrepresentation of ribosome proteins with older age, suggesting that failing anabolic mechanisms are probably preponderant. On the other hand, studies have found UPS‐related proteins and transcription factors overrepresented in quadriceps muscle of older compared with younger persons, while other studies failed to confirm these findings [83, 84]. In conclusion, the mitochondrial quality control system is altered at several levels. While it is reasonable to hypothesize that proteostatis mechanisms play an important role in the maintenance of integrity and efficiency of mitochondria, whether these mechanisms eventually contribute to age‐related sarcopenia remains unknown.
ARE AGE‐RELATED CHANGES IN MITOCHONDRIAL FUNCTION AT THE ROOT OF SARCOPENIA?
As outlined above, there is substantial evidence that mitochondrial function in skeletal muscle declines with aging, and that such decline has important functional consequences on mobility performance. We have examined several possible causes of mitochondrial dysfunction with aging, including a progressive decline of physical function, oxidative stress, anabolic resistance, accumulation of somatic mutations, and alterations of mitochondrial quality control mechanisms including proteostasis, fusion/fission, and mitophagy. Although we have attempted to be as comprehensive as possible in our review of the literature, we are fully aware that this chapter cannot exhaustively explore the enormous literature on the complex relationship between mitochondria, skeletal muscle, and aging. For example, there is evidence that part of the decline in muscle strength with aging is due to a dysfunction of neurological control, both at the central and the peripheral level, and mitochondrial aging presumably contributes to this important cause of sarcopenia. Since the neurological prospective to sarcopenia is addressed in another chapter of this book, we are confident that these aspects will not be ignored in this publication.
Importantly, many of the changes in mitochondria described in this chapter occur in the majority of aging individuals, and not only in those who develop sarcopenia. Thus, the question remains: “Is mitochondrial dysfunction the cause of age‐related sarcopenia?”. In spite of extensive and sophisticated research in this field, a solid answer to such question is still lacking. Of course, if the age‐associated changes described here are overt, the structure and function of mitochondria would be damaged with serious consequences on muscle oxidative capacity, and ultimately on the anatomic integrity and the ability to produce contractile force. Arguably, the lack of success in this field is due to a substantial disagreement between investigators about the appropriate definition of sarcopenia (also addressed elsewhere in this book), and to the fact that few studies have performed muscle biopsies in older persons affected by sarcopenia, which is often associated with poor health status and disability. As mentioned earlier, perhaps the best evidence that sarcopenia is associated with poor mitochondrial function is a gene expression study recently conducted in a multiethnic population where transcripts related to sarcopenia were substantially underrepresented in people with sarcopenia compared with controls [10]. In addition, a metabolomic study conducted in a relatively large population found that carnitine, a mitochondrial lipid transporter essential for the entry of fatty acids, potential fuel and synthetic precursors for the mitochondria, as well as vitamin E, a strong antioxidant important for mitochondrial function, are underrepresented in the serum of frail compared to non‐frail individuals [85]. Indeed, randomized controlled trials are currently in the field that target mitochondrial health to prevent sarcopenia. Ultimately, the results of these studies should provide an answer of whether changes in mitochondrial function are the root causes to sarcopenia.
ACKNOWLEDGMENTS
Supported in part by the Intramural Research Program of the National Institute on Aging, NIH ‐ Baltimore, MD, USA.
The authors would like to thank Miguel Aon and Sonia Cortassa for reading the manuscript and providing very useful suggestions.
REFERENCES
1 1. Dodds, R.M., et al., Global variation in grip strength: a systematic review and meta‐analysis of normative data. Age and Ageing, 2016. 45(2): p. 209–216.
2 2.